bims-musmir 2024-06-09 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–06–09
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA).
Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.
Effects of essential amino acid (EAA) and glutamine supplementation on skeletal muscle wasting in acute, subacute, and postacute conditions.
Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants.
The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.
Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
miR-27b-3p reduces muscle fibrosis during chronic skeletal muscle injury by targeting TGF-βR1/Smad pathway.
Gut microbiota depletion delays somatic peripheral nerve development and impairs neuromuscular junction maturation.
Identification of nicotinamide N-methyltransferase as a promising therapeutic target for sarcopenia.
Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.
Exercise following joint distraction inhibits muscle wasting and delays the progression of post-traumatic osteoarthritis in rabbits by activating PGC-1α in skeletal muscle.
Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis.
cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.
TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.
Plasma taurine level is linked to symptom burden and clinical outcomes in post-COVID condition.

Aging Cell. 2024 Jun 03. e14115

Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA).

Cole J Lukasiewicz, Gregory J Tranah, Daniel S Evans, Paul M Coen, Haley N Barnes, Zhiguang Huo, Karyn A Esser, Xiping Zhang, Christopher Wolff, Kevin Wu, Nancy E Lane, Steven B Kritchevsky, Anne B Newman, Steven R Cummings, Peggy M Cawthon, Russell T Hepple.

  With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

Keywords:  denervation; gene expression profiling; muscle; neuromuscular junction; skeletal

DOI:  https://doi.org/10.1111/acel.14115
Aging Cell. 2024 Jun 03. e14114

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.

Gregory J Tranah, Haley N Barnes, Peggy M Cawthon, Paul M Coen, Karyn A Esser, Russell T Hepple, Zhiguang Huo, Philip A Kramer, Frederico G S Toledo, Xiping Zhang, Kevin Wu, Christopher A Wolff, Daniel S Evans, Steven R Cummings.

  Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.

Keywords:  aging; cohort study; gene expression; mitochondria; muscle; oxidative stress

DOI:  https://doi.org/10.1111/acel.14114
Clin Nutr ESPEN. 2024 May 28. pii: S2405-4577(24)00142-6. [Epub ahead of print]62 224-233

Effects of essential amino acid (EAA) and glutamine supplementation on skeletal muscle wasting in acute, subacute, and postacute conditions.

Massimo Negro, Oscar Crisafulli, Giuseppe D'Antona.

  Under optimal physiological conditions, muscle mass maintenance is ensured by dietary protein, which balances the amino acid loss during the post-absorption period and preserves the body's protein homeostasis. Conversely, in critical clinical conditions (acute, subacute or postacute), particularly those related to hypomobility or immobility, combined with malnutrition, and local/systemic inflammation, the loss of muscle mass and strength can be quantitatively significant. A decline of more than 1% in muscle mass and of more than 3% in muscle strength has been registered in subjects with aged 20-37 yr after just five days of bed rest, similarly to those observed during one year of age-related decline in individuals over the age of 50. Loss of muscle mass and strength can have a dramatic effect on subjects' functional capacities, on their systemic metabolic control and on the amino acid reserve function, all of which are fundamental for the maintenance of other organs' and tissues' cell processes. References available indicate that the average 1%-2% reduction per day of muscle mass in patients in the intensive care unit (ICU) could represent an independent predictor of hospital mortality and physical disability in the five years following hospitalization. After just a few days or weeks of administration, supplementation with EAAs and glutamine has shown significant effects in maintaining muscle size and strength, which are typically negatively affected by some acute/subacute or postacute critical conditions (muscle recovery after surgery, oncology patients, ICU treatments), especially in the elderly or in those with pre-existing degenerative diseases. In this review, we focused on the theoretical bases and the most relevant clinical studies of EAA and glutamine supplementation as a single compound, with the aim of clarifying whether their combined use in a blend (EAAs-glutamine) could be potentially synergistic to prevent disease-related muscle wasting and its impact on the duration and quality of patients' clinical course.

Keywords:  Cancer cachexia; Essential amino acids; Glutamine; Intensive care unit; Malnutrition; Muscle recovery

DOI:  https://doi.org/10.1016/j.clnesp.2024.05.023
Sci Rep. 2024 06 01. 14(1): 12609

Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants.

Dylan Wilburn, Dimitrios Miserlis, Emma Fletcher, Evlampia Papoutsi, Ahmed Ismaeel, Cassandra Bradley, Andrew Ring, Trevor Wilkinson, Robert S Smith, Lucas Ferrer, Gleb Haynatzki, Peter Monteleone, Subhash Banerjee, Elizabeth Brisbois, William T Bohannon, Panagiotis Koutakis.

Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.

DOI: https://doi.org/10.1038/s41598-024-63626-3
Proc Natl Acad Sci U S A. 2024 Jun 11. 121(24): e2321267121

The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.

Ning Li, Ben A Flanagan, Suzanne Edmands.

  Mitochondria perform an array of functions, many of which involve interactions with gene products encoded by the nucleus. These mitochondrial functions, particularly those involving energy production, can be expected to differ between sexes and across ages. Here, we measured mitochondrial effects on sex- and age-specific gene expression in parental and reciprocal F1 hybrids between allopatric populations of Tigriopus californicus with over 20% mitochondrial DNA divergence. Because the species lacks sex chromosomes, sex-biased mitochondrial effects are not confounded by the effects of sex chromosomes. Results revealed pervasive sex differences in mitochondrial effects, including effects on energetics and aging involving nuclear interactions throughout the genome. Using single-individual RNA sequencing, sex differences were found to explain more than 80% of the variance in gene expression. Males had higher expression of mitochondrial genes and mitochondrially targeted proteins (MTPs) involved in oxidative phosphorylation (OXPHOS), while females had elevated expression of non-OXPHOS MTPs, indicating strongly sex-dimorphic energy metabolism at the whole organism level. Comparison of reciprocal F1 hybrids allowed insights into the nature of mito-nuclear interactions, showing both mitochondrial effects on nuclear expression, and nuclear effects on mitochondrial expression. While based on a small set of crosses, sex-specific increases in mitochondrial expression with age were associated with longer life. Network analyses identified nuclear components of strong mito-nuclear interactions and found them to be sexually dimorphic. These results highlight the profound impact of mitochondria and mito-nuclear interactions on sex- and age-specific gene expression.

Keywords:  RNA-seq; hybrid; longevity; mitochondria; sex differences

DOI:  https://doi.org/10.1073/pnas.2321267121
bioRxiv. 2024 May 26. pii: 2024.05.22.595374. [Epub ahead of print]

Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.

Takuya Karasawa, Ran Hee Choi, Cesar A Meza, J Alan Maschek, James E Cox, Katsuhiko Funai.

   Background: Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency.
Methods: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria.
Results: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria.
Conclusions: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.

Keywords:  exercise; mitochondria; phospholipids; skeletal muscle

DOI:  https://doi.org/10.1101/2024.05.22.595374
J Orthop Surg Res. 2024 Jun 02. 19(1): 329

miR-27b-3p reduces muscle fibrosis during chronic skeletal muscle injury by targeting TGF-βR1/Smad pathway.

Hang Yao, Jin Qian, Xu-Ting Bian, Lin Guo, Kang-Lai Tang, Xu Tao.

   BACKGROUND: Fibrosis is a significant pathological feature of chronic skeletal muscle injury, profoundly affecting muscle regeneration. Fibro-adipogenic progenitors (FAPs) have the ability to differentiate into myofibroblasts, acting as a primary source of extracellular matrix (ECM). the process by which FAPs differentiate into myofibroblasts during chronic skeletal muscle injury remains inadequately explored.
METHOD: mouse model with sciatic nerve denervated was constructed and miRNA expression profiles between the mouse model and uninjured mouse were analyzed. qRT/PCR and immunofluorescence elucidated the effect of miR-27b-3p on fibrosis in vivo and in vitro. Dual-luciferase reporter identified the target gene of miR-27b-3p, and finally knocked down or overexpressed the target gene and phosphorylation inhibition of Smad verified the influence of downstream molecules on the abundance of miR-27b-3p and fibrogenic differentiation of FAPs.
RESULT: FAPs derived from a mouse model with sciatic nerves denervated exhibited a progressively worsening fibrotic phenotype over time. Introducing agomiR-27b-3p effectively suppressed fibrosis both in vitro and in vivo. MiR-27b-3p targeted Transforming Growth Factor Beta Receptor 1 (TGF-βR1) and the abundance of miR-27b-3p was negatively regulated by TGF-βR1/Smad.
CONCLUSION: miR-27b-3p targeting the TGF-βR1/Smad pathway is a novel mechanism for regulating fibrogenic differentiation of FAPs. Increasing abundance of miR-27b-3p, suppressing expression of TGF-βR1 and inhibiting phosphorylation of smad3 presented potential strategies for treating fibrosis in chronic skeletal muscle injury.

Keywords:  Fibro-adipogenic progenitors; Fibrosis; MicroRNAs; Muscle injury

DOI:  https://doi.org/10.1186/s13018-024-04733-9
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2363015

Gut microbiota depletion delays somatic peripheral nerve development and impairs neuromuscular junction maturation.

Matilde Cescon, Giovanna Gambarotta, Sonia Calabrò, Chiara Cicconetti, Francesca Anselmi, Svenja Kankowski, Luisa Lang, Marijana Basic, Andre Bleich, Silvia Bolsega, Matthias Steglich, Salvatore Oliviero, Stefania Raimondo, Dario Bizzotto, Kirsten Haastert-Talini, Giulia Ronchi.

  Gut microbiota is responsible for essential functions in human health. Several communication axes between gut microbiota and other organs via neural, endocrine, and immune pathways have been described, and perturbation of gut microbiota composition has been implicated in the onset and progression of an emerging number of diseases. Here, we analyzed peripheral nerves, dorsal root ganglia (DRG), and skeletal muscles of neonatal and young adult mice with the following gut microbiota status: a) germ-free (GF), b) gnotobiotic, selectively colonized with 12 specific gut bacterial strains (Oligo-Mouse-Microbiota, OMM12), or c) natural complex gut microbiota (CGM). Stereological and morphometric analyses revealed that the absence of gut microbiota impairs the development of somatic median nerves, resulting in smaller diameter and hypermyelinated axons, as well as in smaller unmyelinated fibers. Accordingly, DRG and sciatic nerve transcriptomic analyses highlighted a panel of differentially expressed developmental and myelination genes. Interestingly, the type III isoform of Neuregulin1 (NRG1), known to be a neuronal signal essential for Schwann cell myelination, was overexpressed in young adult GF mice, with consequent overexpression of the transcription factor Early Growth Response 2 (Egr2), a fundamental gene expressed by Schwann cells at the onset of myelination. Finally, GF status resulted in histologically atrophic skeletal muscles, impaired formation of neuromuscular junctions, and deregulated expression of related genes. In conclusion, we demonstrate for the first time a gut microbiota regulatory impact on proper development of the somatic peripheral nervous system and its functional connection to skeletal muscles, thus suggesting the existence of a novel 'Gut Microbiota-Peripheral Nervous System-axis.'

Keywords:  Germ-free mice; Schwann cells; gnotobiotic mice; microbiota; myelin; peripheral nerve development; skeletal muscle

DOI:  https://doi.org/10.1080/19490976.2024.2363015
Aging Cell. 2024 Jun 05. e14236

Identification of nicotinamide N-methyltransferase as a promising therapeutic target for sarcopenia.

Rui Liang, Qiao Xiang, Miao Dai, Taiping Lin, Dongmei Xie, Quhong Song, Yu Liu, Jirong Yue.

  Sarcopenia is a significant geriatric syndrome that involves the loss of skeletal muscle mass and strength. Due to its substantial endocrine role, the metabolic microenvironment of skeletal muscle undergoes changes with age. Examining the pathogenesis of sarcopenia through focusing on metabolic dysregulation could offer insights for developing more effective intervention strategies. In this study, we analyzed the transcriptomics data to identify specific genes involved in the regulation of metabolism in skeletal muscle during the development of sarcopenia. Three machine learning algorithms were employed to screen key target genes exhibiting strong correlations with metabolism, which were further validated using RNA-sequencing data and publicly accessible datasets. Among them, the metabolic enzyme nicotinamide N-methyltransferase (NNMT) was elevated in sarcopenia, and predicted sarcopenia with an area under the curve exceeding 0.7, suggesting it as a potential therapeutic target for sarcopenia. As expected, inhibition of NNMT improved the grip strength in aging mice and alleviated age-related decline in the mass index of the quadriceps femoris muscles and whole-body lean mass index. Additionally, the NNMTi treatment increased the levels of nicotinamide adenine dinucleotide (NAD+) content, as well as PGC1α and p-AMPK expression in the muscles of both the D-galactose-treated mouse model and naturally aging mouse model. Overall, this work demonstrates NNMT as a promising target for preventing age-related decline in muscle mass and strength.

Keywords:  NAD+; NNMT; diagnostic biomarker; metabolic dysregulation; sarcopenia

DOI:  https://doi.org/10.1111/acel.14236
Ann Med Surg (Lond). 2024 Jun;86(6): 3753-3756

Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study.

Azita Tavasoli, Maryam Kachuei, Saeed Talebi, Shayan Eghdami.

   Introduction and importance: Cytochrome C oxidase (COX) deficiency is an uncommon inherited metabolic disorder. It is identified by a lack of the COX, also known as Complex IV. This enzyme plays a crucial role in the rate-limiting and oxygen-accepting step of the respiratory chain within the subcellular structures called mitochondria. The deficiency of COX can either be restricted to skeletal muscle tissues or can impact multiple tissues throughout the body.
Case presentation: A 3-year-old girl was admitted due to muscle weakness and a decline in developmental milestones 7 days after a significant stressor. Leukodystrophy was observed in the brain magnetic resonance imaging, and genome sequencing identified a homozygous mutation in exon 1 and 7 of chromosome 17. This mutation led to a deficiency in COX10, which is a component of mitochondrial complex IV.
Clinical discussion: In the medical field, inherited metabolic disorders can be complex to diagnose due to overlapping symptoms with other conditions. Mitochondria's oxidative phosphorylation system, including the COX enzyme complex, plays a crucial role in energy production. Mitochondrial disorders, including COX deficiency, can present at various stages of life with diverse symptoms. Treatment options focus on supportive care and potential benefits from supplements like coenzyme-Q10 and small-molecule therapies targeting mitochondrial function. Identifying genetic mutations is key for advancing treatments in this area.
Conclusion: This report presents a unique case of developmental regression and muscle weakness in a paediatric patient, which can be attributed to a rare occurrence of type 3 nuclear mitochondrial complex IV deficiency.

Keywords:  COX10; case report; cytochrome c oxidase deficiency; mitochondrial complex IV; mitochondrial disorder

DOI:  https://doi.org/10.1097/MS9.0000000000002096
J Orthop Surg Res. 2024 May 31. 19(1): 325

Exercise following joint distraction inhibits muscle wasting and delays the progression of post-traumatic osteoarthritis in rabbits by activating PGC-1α in skeletal muscle.

Xinghui Liu, Rong Chen, Zhenfei Song, Zhibo Sun.

   OBJECTIVE: Muscle wasting frequently occurs following joint trauma. Previous research has demonstrated that joint distraction in combination with treadmill exercise (TRE) can mitigate intra-articular inflammation and cartilage damage, consequently delaying the advancement of post-traumatic osteoarthritis (PTOA). However, the precise mechanism underlying this phenomenon remains unclear. Hence, the purpose of this study was to examine whether the mechanism by which TRE following joint distraction delays the progression of PTOA involves the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as its impact on muscle wasting.
METHODS: Quadriceps samples were collected from patients with osteoarthritis (OA) and normal patients with distal femoral fractures, and the expression of PGC-1α was measured. The hinged external fixator was implanted in the rabbit PTOA model. One week after surgery, a PGC-1α agonist or inhibitor was administered for 4 weeks prior to TRE. Western blot analysis was performed to detect the expression of PGC-1α and Muscle atrophy gene 1 (Atrogin-1). We employed the enzyme-linked immunosorbent assay (ELISA) technique to examine pro-inflammatory factors. Additionally, we utilized quantitative real-time polymerase chain reaction (qRT-PCR) to analyze genes associated with cartilage regeneration. Synovial inflammation and cartilage damage were evaluated through hematoxylin-eosin staining. Furthermore, we employed Masson's trichrome staining and Alcian blue staining to analyze cartilage damage.
RESULTS: The decreased expression of PGC-1α in skeletal muscle in patients with OA is correlated with the severity of OA. In the rabbit PTOA model, TRE following joint distraction inhibited the expressions of muscle wasting genes, including Atrogin-1 and muscle ring finger 1 (MuRF1), as well as inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in skeletal muscle, potentially through the activation of PGC-1α. Concurrently, the production of IL-1β, IL-6, TNF-α, nitric oxide (NO), and malondialdehyde (MDA) in the synovial fluid was down-regulated, while the expression of type II collagen (Col2a1), Aggrecan (AGN), SRY-box 9 (SOX9) in the cartilage, and superoxide dismutase (SOD) in the synovial fluid was up-regulated. Additionally, histological staining results demonstrated that TRE after joint distraction reduced cartilage degeneration, leading to a significant decrease in OARSI scores.TRE following joint distraction could activate PGC-1α, inhibit Atrogin-1 expression in skeletal muscle, and reduce C-telopeptides of type II collagen (CTX-II) in the blood compared to joint distraction alone.
CONCLUSION: Following joint distraction, TRE might promote the activation of PGC-1α in skeletal muscle during PTOA progression to exert anti-inflammatory effects in skeletal muscle and joint cavity, thereby inhibiting muscle wasting and promoting cartilage regeneration, making it a potential therapeutic intervention for treating PTOA.

Keywords:  Exercise; Joint distraction; Muscle wasting; PGC-1α; Post-traumatic osteoarthritis

DOI:  https://doi.org/10.1186/s13018-024-04803-y
Nat Aging. 2024 Jun 04.

Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis.

Sven Wischnewski, Thomas Thäwel, Chiseko Ikenaga, Anna Kocharyan, Celia Lerma-Martin, Amel Zulji, Hans-Werner Rausch, David Brenner, Leonie Thomas, Michael Kutza, Brittney Wick, Tim Trobisch, Corinna Preusse, Maximilian Haeussler, Jan Leipe, Albert Ludolph, Angela Rosenbohm, Ahmet Hoke, Michael Platten, Jochen H Weishaupt, Clemens J Sommer, Werner Stenzel, Thomas E Lloyd, Lucas Schirmer.

Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.

DOI: https://doi.org/10.1038/s43587-024-00645-9
Proc Natl Acad Sci U S A. 2024 Jun 11. 121(24): e2400732121

cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.

Diana M Ho, Muhammad Shaban, Faisal Mahmood, Payel Ganguly, Leonardo Todeschini, David Van Vactor, Spyros Artavanis-Tsakonas.

  Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.

Keywords:  ALS; TDP-43; cAMP/PKA signaling; neurodegeneration; proteinopathy

DOI:  https://doi.org/10.1073/pnas.2400732121
Mol Brain. 2024 Jun 05. 17(1): 32

TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.

Vincent E Provasek, Manohar Kodavati, Brandon Kim, Joy Mitra, Muralidhar L Hegde.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.

Keywords:  Amyotrophic lateral sclerosis (ALS); Co-immunoprecipitation (CoIP); DNA double-strand breaks (DSBs); DNA mismatch repair (MMR); Neurodegeneration; Proximity ligation assay (PLA); TDP-43

DOI:  https://doi.org/10.1186/s13041-024-01108-3
PLoS One. 2024 ;19(6): e0304522

Plasma taurine level is linked to symptom burden and clinical outcomes in post-COVID condition.

Mobin Khoramjoo, Kaiming Wang, Karthik Srinivasan, Mahmoud Gheblawi, Rupasri Mandal, Simon Rousseau, David Wishart, Vinay Prasad, Lawrence Richer, Angela M Cheung, Gavin Y Oudit.

BACKGROUND: A subset of individuals (10-20%) experience post-COVID condition (PCC) subsequent to initial SARS-CoV-2 infection, which lacks effective treatment. PCC carries a substantial global burden associated with negative economic and health impacts. This study aims to evaluate the association between plasma taurine levels with self-reported symptoms and adverse clinical outcomes in patients with PCC.
METHODS AND FINDINGS: We analyzed the plasma proteome and metabolome of 117 individuals during their acute COVID-19 hospitalization and at the convalescence phase six-month post infection. Findings were compared with 28 age and sex-matched healthy controls. Plasma taurine levels were negatively associated with PCC symptoms and correlated with markers of inflammation, tryptophan metabolism, and gut dysbiosis. Stratifying patients based on the trajectories of plasma taurine levels during six-month follow-up revealed a significant association with adverse clinical events. Increase in taurine levels during the transition to convalescence were associated with a reduction in adverse events independent of comorbidities and acute COVID-19 severity. In a multivariate analysis, increased plasma taurine level between acute and convalescence phase was associated with marked protection from adverse clinical events with a hazard ratio of 0.13 (95% CI: 0.05-0.35; p<0.001).
CONCLUSIONS: Taurine emerges as a promising predictive biomarker and potential therapeutic target in PCC. Taurine supplementation has already demonstrated clinical benefits in various diseases and warrants exploration in large-scale clinical trials for alleviating PCC.

DOI: https://doi.org/10.1371/journal.pone.0304522